Dendritic Ca signals in striatal medium spiny neurons

描述(申请人提供)：纹状体是大脑的一个关键区域，在启动和执行自愿运动中起着核心作用。中棘神经元(MSN)是纹状体中最常见的细胞类型，它们引起纹状体向参与运动协调的其他脑区发送抑制性投射。MSN的退化或功能紊乱会发生在几种人类运动障碍中，包括亨廷顿氏症和帕金森氏症，以及某些精神疾病和药物成瘾。像大多数神经元一样，刺激诱发的钙离子进入MSN调节许多过程，包括神经元的兴奋性、电路连接和基因转录。最近，在亨廷顿病患者和该疾病的小鼠模型中都发现了钙离子的摄取。有趣的是，这种缺陷在任何运动症状出现之前就可以检测到，并可能暗示钙调节的改变直接导致了在疾病后期出现的神经元功能障碍。尽管已经存在成熟的技术来研究神经元中的钙处理，但MSN树突中钙信号的特性仍然相对未知。这项拟议的工作将结合使用双光子激光扫描显微镜、双光子激光去势和全细胞电生理学来分析MSN如何整合许多突触的活动。我们的研究将研究MSN中发现的多种类型的电压门控离子通道和突触活动之间的非线性相互作用如何决定膜去极化和钙信号。一项新的技术将被用来确定树突上活跃突触的空间排列是否决定了突触活动对膜去极化的净影响。此外，我们将研究这些非线性是否在突触可塑性的诱导中发挥作用。最后，我们将研究多巴胺对突触整合和钙离子处理的影响。最终，我们希望了解MSN的特殊电生理和形态特性如何影响纹状体功能，以及这些过程的扰动如何导致人类疾病。

DESCRIPTION (provided by applicant): The striatum is a key brain area that plays a central role in the initiation and execution of voluntary movements. Medium spiny neurons (MSNs) are the most common cell type in the striatum and they give rise to the inhibitory projection that striatum sends to other brain areas involved in motor coordination. Degeneration or perturbed function of MSNs occurs in several human movement disorders including Huntington's and Parkinson's as well as in certain psychiatric illnesses and drug addiction. As in most neurons, stimulus-evoked calcium entry into MSNs regulates many processes including neuronal excitability, circuit connectivity, and gene transcription. Recently, perturbed calcium handling has been identified in patients with Huntington's disease as well as in mouse models of the disease. Interestingly this defect is detectable before the appearance of any motor symptoms and may hint that altered calcium regulation directly leads to the neuronal dysfunction seen in later stages of the disease. Despite the existence of well-established techniques for the study of calcium handling in neurons, the properties of calcium signaling in dendrites of MSNs remain relatively unexplored. The proposed work will use a combination of 2-photon laser scanning microscopy, 2-photon laser uncaging, and whole-cell electrophysiology to analyze how MSNs integrate the activity of many synapses. Our study will examine how nonlinear interactions between the many types of voltage-gated ion channels found in MSNs and synaptic activity dictate both membrane depolarization and calcium signaling. A novel technique will be used to determine if the spatial arrangement of active synapses on the dendrite determines the net effect of synaptic activity on membrane depolarization. Furthermore we will examine whether these nonlinearities play a role in the induction of synaptic plasticity. Lastly, the effect of dopamine on synaptic integration and calcium handling will be examined. Ultimately, we hope to understand how the specialized electrophysiological and morphological properties of MSNs influence striatal function and how perturbation of these processes contributes to human disease.